ArticleNucleic acids research2021
NMPylation and de-NMPylation of SARS-CoV-2 nsp9 by the NiRAN domain.
Article in Nucleic acids research, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 51 citations in OpenAlex.
- Structural and Mechanistic Perspectives on SARS-CoV-2 Nonstructural Protein 14-Mediated Cap Formation and Drug Discovery.Microorganisms · 2026Review
- Article
- Polypeptide encoded by the -1 PRF signal of SARS-CoV-2 controls multiple enzymatic activities of the viral NiRAN domain.NAR molecular medicine · 2025Article
- The mechanism for GTP-mediated RNA capping by the SARS-CoV-2 NiRAN domain remains unresolved.Cell · 2025Article
- Construction and validation of a cell based reporter assay for identifying inhibitors of SARS coronavirus 2 RNA dependent RNA polymerase activity.Scientific reports · 2025Article
- Article
- Mutations in nonstructural proteins essential for pathogenicity in SARS-CoV-2-infected mice.Journal of virology · 2024Article
- Inhibition of SARS-CoV-2 Nsp9 ssDNA-Binding Activity and Cytotoxic Effects on H838, H1975, and A549 Human Non-Small Cell Lung Cancer Cells: Exploring the Potential ofInternational journal of molecular sciences · 2024Article
- SARS-CoV-2 biology and host interactions.Nature reviews. Microbiology · 2024Review
- SHIFTR enables the unbiased identification of proteins bound to specific RNA regions in live cells.Nucleic acids research · 2024Article
- A structural analysis of the nsp9 protein from the coronavirus MERS CoV reveals a conserved RNA binding interface.Proteins · 2024Article
- Structural and functional insights into the enzymatic plasticity of the SARS-CoV-2 NiRAN domain.Molecular cell · 2023Article
- Article
- Discovery of a Druggable, Cryptic Pocket in SARS-CoV-2 nsp16 Using Allosteric Inhibitors.ACS infectious diseases · 2023Article
- Targeting SARS-CoV-2 Non-Structural Proteins.International journal of molecular sciences · 2023Review
- Conserved Characteristics of NMPylation Activities of Alpha- and Betacoronavirus NiRAN Domains.Journal of virology · 2023Article
- Redefining pseudokinases: A look at the untapped enzymatic potential of pseudokinases.IUBMB life · 2023Review
- Kill or corrupt: Mechanisms of action and drug-resistance of nucleotide analogues against SARS-CoV-2.Antiviral research · 2023Review
- Inside-out: Antibody-binding reveals potential folding hinge-points within the SARS-CoV-2 replication co-factor nsp9.PloS one · 2023Article
- Classification, replication, and transcription ofFrontiers in microbiology · 2023Review
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
The catalytic subunit of SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) contains two active sites that catalyze nucleotidyl-monophosphate transfer (NMPylation). Mechanistic studies and drug discovery have focused on RNA synthesis by the highly conserved RdRp. The second active site, which resides in a Nidovirus RdRp-Associated Nucleotidyl transferase (NiRAN) domain, is poorly characterized, but both catalytic reactions are essential for viral replication. One study showed that NiRAN transfers NMP to the first residue of RNA-binding protein nsp9; another reported a structure of nsp9 containing two additional N-terminal residues bound to the NiRAN active site but observed NMP transfer to RNA instead. We show that SARS-CoV-2 RdRp NMPylates the native but not the extended nsp9. Substitutions of the invariant NiRAN residues abolish NMPylation, whereas substitution of a catalytic RdRp Asp residue does not. NMPylation can utilize diverse nucleotide triphosphates, including remdesivir triphosphate, is reversible in the presence of pyrophosphate, and is inhibited by nucleotide analogs and bisphosphonates, suggesting a path for rational design of NiRAN inhibitors. We reconcile these and existing findings using a new model in which nsp9 remodels both active sites to alternately support initiation of RNA synthesis by RdRp or subsequent capping of the product RNA by the NiRAN domain.
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